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Cardiolipin as a biomarker of mitochondrial dysfunction associated with Parkinson's disease.

A commonly used pesticide, rotenone, is a mitochondrial respiratory complex I inhibitor capable of selective oxidation of mitochondrial phospholipid, cardiolipin (CL). Given that rotenone exposure is associated with the development of Parkinson disease (PD), we hypothesized that CL peroxidized molecular species accompanying mitochondrial dysfunction may represent a new biomarker of PD. In this study, we used circulating lymphocytes isolated from human blood and found that rotenone (50-250microM, 12-18h) caused apoptosis (phosphatidylserine externalization, caspase 3/7 activation), reactive oxygen species production (superoxide, H2O2), mitochondrial dysfunction (inactivation of complex I, decrease of mitochondria membrane potential, depletion of ATP) and activation of peroxidase activity of mitochondria. Using an oxidative lipidomics approach, we found that treatment of lymphocytes with rotenone resulted in accumulation of monolyso-CL and oxygenated free fatty acids. In addition we were able to detect oxygenated molecular species of tetra-linoleyl CL, a major CL molecular species in lymphocytes. Notably, molecular species of oxygenated CL formed in human lymphocytes were similar to those formed in cyt c driven reaction in the presence of H2O2 - in line with the known participation of cytochrome as a catalyst of CL peroxidation during apoptosis. Using the combination of lipidomics and oxidative epitope-targeted enzymatic digestion of oxidized tetralinoleoyl-CL we found that its oxygenated LA species were represented by hydroxy- and hydroperoxy-derivatives. Thus, we conclude that CL and its oxygenation products and metabolites may represent a new biomarker of rotenone-induced mitochondrial dysfunction associated with PD.